TrpA1 activation in peripheral sensory neurons underlies the ionic basis of pain hypersensitivity in response to vinca alkaloids.

Nina Boiko,Jean C Bopassa,Elizabeth Montano,Jay Z Parrish,Kenneth M Hargreaves,Claire R Williams,Charles C Kim,Geraldo Medrano,James D Stockand,Nan Jiang,Ngonidzashe B Madungwe,Benjamin A Eaton,Alexander G Obukhov

doi:10.1371/journal.pone.0186888

Abstract

Chemotherapy induced peripheral neuropathy (CIPN), a side effect of many anti-cancer drugs including the vinca alkaloids, is characterized by a severe pain syndrome that compromises treatment in many patients. Currently there are no effective treatments for this pain syndrome except for the reduction of anti-cancer drug dose. Existing data supports the model that the pain associated with CIPN is the result of anti-cancer drugs augmenting the function of the peripheral sensory nociceptors but the cellular mechanisms underlying the effects of anti-cancer drugs on sensory neuron function are not well described. Studies from animal models have suggested a number of disease etiologies including mitotoxicity, axonal degeneration, immune signaling, and reduced sensory innervations but these outcomes are the result of prolonged treatment paradigms and do not necessarily represent the early formative events associated with CIPN. Here we show that acute exposure to vinca alkaloids results in an immediate pain syndrome in both flies and mice. Furthermore, we demonstrate that exposure of isolated sensory neurons to vinca alkaloids results in the generation of an inward sodium current capable of depolarizing these neurons to threshold resulting in neuronal firing. These neuronal effects of vinca alkaloids require the transient receptor potential ankyrin-1 (TrpA1) channel, and the hypersensitization to painful stimuli in response to the acute exposure to vinca alkaloids is reduced in TrpA1 mutant flies and mice. These findings demonstrate the direct excitation of sensory neurons by CIPN-causing chemotherapy drugs, and identify TrpA1 as an important target during the pathogenesis of CIPN.

Highlights

Chemotherapy induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of many anti-cancer drugs, including vinblastine and vincristine, that is associated with a severe peripheral pain syndrome [1]
We show that the acute exposure of peripheral sensory neurons to vinca alkaloid class of anti-cancer drugs results in a robust pain syndrome that is characterized by a rapid increase in the sensitivity to both mechanical and thermal stimuli
Mutational deletion of the transient receptor potential ankyrin-1 (TrpA1) gene significantly reduces this effect of vinca alkaloids in both mice and Drosophila larvae revealing an ancient and conserved requirement of TrpA1 for these acute effects of vinca alkaloids on pain hypersensitivity

Summary

Introduction

Chemotherapy induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of many anti-cancer drugs, including vinblastine and vincristine, that is associated with a severe peripheral pain syndrome [1]. The class IV dendrite arborization (C4da) sensory neurons in Drosophila melanogaster larvae are polymodal sensory neurons required for response to a broad range noxious stimuli during the larval stage of development [18]. These neurons were initially characterized based upon their stereotyped dendritic morphology but have been shown to be critical sensory neurons endowing the larvae with a surprisingly large repertoire of sensory modalities [18,19,20]. The larval C4da neurons faithfully mimic the properties of mammalian DRG nociceptors including the responsiveness to multiple sensory modalities including temperature, chemical, and mechanical stimuli [21,22,23]. The similarities with mammalian sensory neurons and the experimental tractability of the Drosophila model organism make the C4da neuron a powerful system for the study of pain during CIPN

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